Search

Background: Distal tibial primary bone tumors are rare, and options for limb salvage surgery are limited and challenging. Importantly, local control has shown to be crucial and necessary for cure, and radical surgery is one of the most important components of therapy for some bone sarcomas. We investigated the feasibility and functional and oncological outcomes of distal tibial reconstruction using endoprosthesis in children with malignant bone tumors. Methods: Fourteen patients (median age 13.6 years) with primary bone tumors (4 Ewing sarcoma [ES], 10 osteosarcoma) of the distal tibiae were treated during 2013-2019. All patients had reconstruction using a modular (13 patients) or expandable custom-made titanium bone replacement system (1 patient). All patients received chemotherapy before and after surgery. Results: Twelve patients (85.7%) are alive with a median follow-up 20 months from diagnosis. Five-year estimates of event-free survival and overall survival were 60.6% and 76.4%, respectively. Three patients had postoperative complications requiring second surgery. Maximum dorsiflexion and plantar flexion of the foot were 20 degrees (range 0-20 degrees) and 20 degrees (range 5-20 degrees), respectively. Conclusion: For select distal tibial sarcomas, after neoadjuvant chemotherapy pretreatment and radical resection, reconstruction using an endoprosthesis as a radical surgery provides an option was associated with a low rate of short-term local complications and relatively good early function. Level of Evidence: Level IV, therapeutic study.

IntroductionEpidemiological analysis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections in pediatric hematology and oncology (PHO) and hematopoietic cell transplant (HCT) centers in a Polish nationwide study, as well as analysis of the preventive strategies in these centers.MethodsAll of the 18 PHO/HCT centers participated in eight surveys and questionnaires conducted over the first 5 months of the SARS-CoV-2/coronavirus disease 2019 (COVID-19) pandemic in Poland. Epidemiological data were collected at eight regular time points, and the strategy of preventive management was done once after 4 months of the pandemic.ResultsDuring this analyzed period, eight patients were positive for SARS-CoV-2. The estimated incidence of SARS-CoV-2 positivity in Polish PHO/HCT centers was 0.5%. After exclusion of HCT patients (with one patient being infected), the estimated incidence of SARSCoV-2 positivity was between 0.5 and 0.6%. In all but one case, the course of COVID-19 was asymptomatic or mild, and it was moderate in one case. None of them developed SARS or respiratory insufficiency, none of them required treatment in the intensive care unit (ICU), and no patient died due to SARS-CoV-2 infection. As of July 1, parents staying in the hospital together with their children were regularly tested for the virus in 13 centers. Asymptomatic healthcare personnel were regularly tested for the virus in seven centers.ConclusionsThe estimated incidence of SARS-CoV-2 infection among PHO/HCT patients is lower than in Western Europe; however, these patients cannot be regarded as a low-risk group. The low COVID-19 incidence should be interpreted as a result of strictly and continuously implemented detailed preventive measures in the PHO/HCT wards and in hospitals.

Background Langerhans cell histiocytosis (LCH) affects 1–2 in 1,000,000 people. The disease is not associated with increased risk of treatment failure (especially among older children), but appropriate procedures implemented in advance can eliminate complications which might appear and significantly worsen the patients’ quality of life. Thus, we sought to evaluate the clinical features, management, and outcome of children with LCH treated in Polish pediatric hematology-oncology centers. Materials and methods One hundred eighty two patients with LCH were treated according to the Histiocytic Society Guidelines between 2010 and 2017. The participating centers were requested to provide the following data: demographic, clinical, as well as local or systemic treatment data and patients’ outcome. Overall survival (OS) and event free survival (EFS) were estimated by Kaplan-Meier methods and compared using the log-rank test. Results Sixty nine percent of children were classified as single system (SS). The patients with SS disease were significantly older as compared to the children with multisystem disease (MS), 6 vs. 2.3 years respectively (p 0.003). Bones were involved in 76% of patients. Systemic treatment was applied to 47% of children with SS disease and 98% with MS disease. Fourteen patients relapsed while two children died. OS and EFS in entire group were 0.99 and 0.91 respectively (with median follow-up 4.3 years). Conclusion The treatment of LCH in Polish centers was effective, however, new approaches, including mutation analyses and good inter-center cooperation, are needed to identify patients who might require modification or intensification of treatment.

PURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Background: In recent years, modifications of treatment protocols introduced in pediatric oncology have resulted in a significant improvement in treatment outcomes. Unfortunately, the probability of subsequent malignant neoplasm (SMN) in this group of patients is 3 to 6 times higher than the general age-matched population. In this study, we sought to evaluate the treatment options for patients with secondary bone tumors after prior anti-cancer therapy. Materials and Methods: Twenty-four patients (median age 12.9 years) with subsequent malignant bone tumors were treated according to oncological guidelines for bone sarcoma during the period 1991–2020. All patients had a standard tumor imaging and laboratory evaluation. All toxicities were documented. Results: The median time from the first neoplasm to SMN was 7.6 years (range 2.4 to 16.3 years). All patients received chemotherapy and underwent surgery as a local control procedure. Two patients with Ewing sarcoma had additional radiation on the tumor bed. A complete response was achieved in 20 patients. With a median follow-up of 18.3 years (range 5.7 to 40.3 years), 18 patients (75%) are alive. The estimated 5-year post-subsequent bone malignant neoplasm survival was 74.5% (95% CI 55–95%). Fourteen patients required chemotherapy dose modification, and doxorubicin was discontinued in seven patients. One patient required a renal transplant two years after treatment. There were no other significant toxicities. Conclusions: The treatment of bone SMNs can be effective, although in many patients it is necessary to reduce the doses of drugs. Early detection and aggressive treatment can improve the outcome.

The effect of age on the incidence of late sequelae that occur after anticancer treatment in childhood is still not fully elucidated. In this multicenter study of long-term survivors diagnosed before age of three, we investigated the prevalence of late effects many years after treatment.The study group (n = 561) was selected from the Polish National Childhood Cancer Survivors Registry (n = 1761) created in 2007. A survivor was defined as an individual who has survived at least 5 years after completion of anticancer treatment. All children were diagnosed between 1991 and 2016, mean age at diagnosis was 1.82 years (range 0.03-2.99) and median follow up time - 9.85 years (range 5.0-23.6). They were treated in accordance with international protocols approved by the Polish Pediatric Leukemia and Lymphoma Group and Polish Solid Tumor Group. Chemotherapy alone was used in 192 (34.2%), chemotherapy and radiotherapy - 56 (10%), chemotherapy and surgery - 176 (31.4%), chemotherapy, radiotherapy, and surgery - 79 (14.1%), and surgery alone in 58 patients (10.3%).Of all patients enrolled to the study, only 94 (16.8%) had normal function of all organs. Seventy-six (13.5%) children developed dysfunction in one organ, another 83 (14.8%) had symptoms or complaints suggestive of dysfunction in two organs or systems, 88 (15.7%) had abnormalities in three organs, and 220 (39.2%) had at least four or more dysfunctions. In the entire study group, dysfunctions most frequently (20% of cases) involved the following organs/systems: circulatory - 21.8%, urinary - 30.8%, gastrointestinal - 20.8%, immune - 23.5%, vision - 20.7%, hearing - 21.8%, and oral and masticatory dysfunction - 26.9%. We did not find any significant differences in organ dysfunction between children diagnosed under the age of 1 and those diagnosed at the age of 1-3, except for a lower incidence of thyroid abnormalities (p = 0.007) and the higher prevalence of liver dysfunction in youngest patients. In the subset with longer follow-up period (10 years) more frequent thyroid abnormalities (p = 0.019), male (p = 0.002) and female (p = 0.026) gonads dysfunction, as well as musculoskeletal problems (p 0.001) were observed. Among subjects who received radiotherapy compared to those who did not, short stature (p = 0.001), and dysfunction of the following systems/organs - circulatory (p = 0.049), urinary (p = 0.012), thyroid gland (p 0.0001), nervous (p = 0.007), immunological (p = 0.002), liver (p = 0.03), dental or chewing difficulties (p = 0.001), hearing (p = 0.001) and musculoskeletal (p = 0.026) were more frequently reported. When multimodal therapy was applied (chemotherapy, radiotherapy, and surgery) a higher incidence of short stature (p = 0.007), urinary system disorders (p 0.0001), thyroid dysfunction (p 0.0001), hearing loss (p 0.0001), and skin problems (p = 0.031) were observed.This study confirms that radiotherapy and some specific toxicity of cytostatics are the most important factors affecting organ function. Apart from a higher incidence of liver dysfunction in the youngest patients, there were no significant differences in organ and system toxicities between children diagnosed under the age of 1 and those diagnosed at the age of 1-3. We have shown that this group requires systematic, careful and long-term follow-up.

Osteosarcoma (OS) is a bone tumour affecting adolescents and elderly people. Unfortunately, basic treatment methods are still underdeveloped, which has a high impact on the poor survivability of the patients. Studies designed to understand the underlying mechanisms of osteosarcoma development, as well as preclinical investigations aimed at establishing novel therapeutic strategies, rely significantly upon in vitro models, which apply well-established cell lines such as U-2 OS, Saos-2 and MG-63. In this study, the expression of chosen markers associated with tumour progression, metastasis and survival were identified using RT-qPCR. Levels of several onco-miRs (miR-21-5p, miR-124-3p, miR-223-3p and miR-320a-3p) and long non-coding RNA MEG3 were established. The mRNA expression of bone morphogenetic proteins (BMPs), including BMP-2, BMP-3, BMP-4, BMP-6, BMP-7, as well as their receptors: BMPR-IA, BMPR-IB and BMPR-II was also determined. Other tested markers included metalloproteinases, i.e., MMP-7 and MMP-14 and survivin (BIRC5), C-MYC, as well as CYCLIN D (CCND1). The analysis included comparing obtained profiles with transcript levels established for the osteogenic HeLa cell line and human adipose-derived stromal cells (hASCs). The tested OS cell lines were characterised by a cancer-related phenotype, such as increased expression of mRNA for BMP-7, as well as MMP-7 and MMP-14. Osteosarcoma cells differ considerably in miR-21-5p and miR-124-3p levels, which can be related to uncontrolled tumour growth. The comprehensive examination of osteosarcoma transcriptome profiles may facilitate the selection of appropriate cell models for preclinical investigations aimed at the development of new strategies for OS treatment.

Ewing sarcoma (ES) is a rare and aggressive disease that requires multidisciplinary treatment with the use of chemotherapy, radiotherapy, and surgery. Our retrospective study aimed to analyze the prognostic factors and treatment results in different age groups of patients. Between 1998 and 2018, 569 patients with ES were treated in two referral centers. The patients were divided into four age groups (≤10 years, 11–18 years, 19–25, and &gt, 25). The treatment results and prognostic factors were assessed for each group. For statistical analyses, we used the Chi2 test, the Kaplan–Meier estimator with a log-rank test, and the multivariate Cox model. Five-year overall survival (OS) rate was 56%. In the age subgroups: ≤10 years, 11–18 years, 19–25 years, and &gt, 25 years, the 5-year OS rates were 75%, 58%, 41%, and 52%, respectively. Favorable prognostic factors: female gender (p = 0.024), non-axial localization (p = 0.005), VIDE regimen (p &lt, 0.001), and surgery as a local treatment (p &lt, 0.001) dominated in the group ≤10 years. In multivariate analysis, male (HR = 1.53), axial localization (HR = 1.46), M1 status at presentation (HR = 2.64), and age &gt, 10 years (HR = 2.29) were associated with shorter OS. The treatment results in ES are significantly better in children aged ≤10 years, the challenge is to provide therapy for adolescents and young adults. The diagnostics and treatment of ES patients must be provided in referral centers.

Background. Although not all children can be cured yet, much more emphasis is placed on the quality of life during and after cancer treatment. In the case of recurrence, mutilating treatment is still the prevalent option. In our study, we explored the role of limb salvage surgery for young patients with metastatic malignant bone tumors after endoprosthesis reconstruction during the first line of treatment and evaluated the impact of the local control modality in disease control and functional outcomes. Materials and Methods. Eleven patients with bone tumor treated between 2007 and 2018 were included in this study. Both during primary treatment and during recurrence, limb salvage surgery was performed using a modular or expandable custom-made replacement system. Peri- and postoperative care for both surgeries were similar. All patients were given chemotherapy before and after both surgeries, according to the oncological guidelines. Results. Seven patients (63.6%) are alive with a median follow-up of 6.5 years from diagnosis. None had local recurrence. Five-year estimates of event-free survival and overall survival were 36.27% and 79.55%, respectively. Median time between the first and second surgery was 2.7 years. Three patients presented with postoperative complications following both surgeries and required resurgical intervention. Three months following the second surgery, the Musculoskeletal Tumor Society Scale (MSTS) scores were 15–27 points (21 points on average—60%). Conclusions. Limb salvage surgery is feasible and offers good chance of cure with a reasonable rate of complications and good function in patients with recurrent bone sarcoma after endoprosthesis reconstruction during the first line of treatment.

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

Simple Summary Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare neoplasm that most commonly develops within maxilla in infants. It usually has a benign clinical course and is treated with only surgery. However, patients with large, inoperable, metastatic or multiply recurring MNTI may require systemic treatment. The role of pre- and post-surgery chemotherapy (CHT) in the management of MNTI is unclear. Here, we have presented the disease courses and outcomes of four infants treated with multidrug CHT due to inoperable/recurrent MNTI. Additionally, a systematic literature review was performed which revealed 38 similar cases in the last 42 years. Most children with primarily inoperable MNTI responded to CHT, which allowed physicians to perform complete, non-mutilating delayed surgery. However, it is still uncertain whether CHT administered after incomplete resection of MNTI prevents recurrence. This study aimed to contribute to the establishment of standards of management in patients with inoperable, metastatic or persistently recurring MNTIs, which are currently lacking. Abstract Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare pediatric neoplasm of neural crest origin. In most cases, it develops in infants as a localized tumor of the maxilla, and surgery is usually curative. In less than 10% of patients with inoperable, metastatic or persistently recurring MNTI, chemotherapy (CHT) may be considered; however, its role is still unclear. The aim of our study was to assess the efficacy of CHT in children with large, inoperable, metastatic and/or recurrent MNTI. Four such infants, treated with CHT in Polish and German centers of pediatric oncology, were presented. Additionally, a systematic literature search of the PubMed/MEDLINE, Scopus and Web of Science databases was performed, yielding 38 similar cases within the last 42 years. Neoadjuvant CHT, based mainly on the protocols for neuroblastoma, was often effective, allowing for complete delayed surgery in most cases. However, the role of adjuvant CHT in preventing recurrences after incomplete resection of MNTI remains unclear. Disseminated inoperable MNTI was almost universally associated with poor response to CHT and unfavorable outcome. Further investigations to elaborate standards of management in patients with inoperable, metastatic or persistently recurring MNTIs are necessary to improve outcomes.

(1) Background: The study proposed to analyze microvessel density (MVD) in rhabdomyosarcoma (RMS) based on the expression of angiogenesis markers and define its prognostic role in this group of patients. (2) Methods: The study included forty-nine pediatric patients diagnosed with RMS. Tumor tissue expression of CD31, CD34, and CD105 was analyzed. MVD was calculated and correlated with clinical RMS prognostic parameters. (3) Results: CD31, CD34, and CD105 are expressed in all RMS cases. MVD/CD105 was significantly higher in the RMS group than in the control group. The mean and median values of MVD/CD105 in RMS were lower than MVD/CD31 and MVD/CD34. MVD/CD105 was significantly higher in patients with alveolar RMS and those with metastatic disease. Patients with higher levels of MVD/CD105 had a higher risk of death (HR = 1.009). (4) Conclusion: CD105 is a relevant angiogenesis marker in pediatric RMS, and MVD/CD105 is an independent risk factor of short overall survival in children with RMS.

Background: Due to the rarity of osteosarcoma and limited indications for radiotherapy (RT), data on RT for this tumor are scarce. This study aimed to investigate the utilization of RT for osteosarcomas in the recent 20 years and to identify factors related to patients’ response to radiation. Methods: We performed a retrospective analysis of patients irradiated for osteosarcoma treatment. We planned to assess differences in the utilization of RT between the periods of 2000–2010 and 2011–2020, identify the risk factors associated with local progression (LP), determine whether RT-related parameters are associated with LP, and calculate patients’ survival. Results: A total of 126 patients with osteosarcoma who received 181 RT treatments were identified. We found a difference in RT techniques between RT performed in the years 2000–2010 and that performed in the years 2011–2020. LP was observed after 37 (20.4%) RT treatments. Intent of RT, distant metastases, and concomitant systemic treatment affected the risk of LP. Five-year overall survival was 33% (95% confidence interval (26%–43%)). Conclusions: RT for osteosarcoma treatment has evolved from simple two-dimensional palliative irradiation into more conformal RT applied for new indications including oligometastatic and oligoprogressive disease. RT may be a valuable treatment modality for selected patients with osteosarcoma.

Pediatric germ cell tumors (GCTs) are a group of chemosensitive malignancies with a 90% curability rate. We report a series of children with relapsing or therapy-resistant GCT treated with melphalan&ndash, etoposide&ndash, carboplatin high-dose chemotherapy (HDCT) and autologous stem cell transplantation. This consisted of 18 children, either with GCTs after relapse (nine patients) or with an unsatisfactory response to first-line chemotherapy (nine patients), who underwent HDCT. The HDCT regimens MEC1 (carboplatin 1500 mg/m2, etoposide 1800 mg/m2, and melphalan 140 mg/m2) and MEC2 (carboplatin 800 mg/m2, etoposide 800 mg/m2, and melphalan 140 mg/m2) were each used in nine patients. The median observation time was 81 months, the 5-year overall survival (OS) was 76%, and the event-free survival (EFS) was 70.8%. Non-relapse mortality was 0%, and four patients died after HDCT due to progression of the malignancy. No difference in OS or EFS was noted between the MEC1 and MEC2 protocols. The 5-year OS and 5-year EFS were higher in children treated with autologous stem cell transplantation before the age of four years. The presence of metastatic disease or time of HDCT consolidation during first/subsequent line chemotherapy did not affect patient survival. The melphalan&ndash, carboplatin protocol is feasible in pediatric GCT, but is associated with potentially life-threatening complications. In conclusion, the use of HDCT must be examined in well-designed clinical trials, and the identification of patients who can benefit from this approach is critical to avoid overtreatment.

Background/aim Nivolumab is an immune checkpoint inhibitor with high antitumor activity in selected neoplasms. The aim of the study was to evaluate the efficacy and safety of nivolumab in pediatric patients with various types of highly malignant advanced tumors. Patients and methods Ten patients with a median age of 15.1 years were included in the study. The indications for treatment were: malignant skin melanoma (n=5), brain tumor (n=2), malignant melanoma of the brain (n=1), Hodgkin lymphoma (n=1) and soft tissue sarcoma (n=1). Results Complete disease remission was observed in 4 patients. Overall survival at 24 months from diagnosis for the entire group was 0.36. Two patients receiving combination therapy of nivolumab and ipilimumab did not achieve a remission. Adverse events of immunotherapy were observed in 4/10 patients. Conclusion Nivolumab is a promising option in pediatric advanced malignancies. Treatment with immunotherapy was relatively well tolerated, and emerging side-effects were manageable.

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder classified as non-Langerhans cell histiocytosis; although it is usually a benign and self-limiting disease, it can be fatal in some cases, especially with systemic dissemination. We present a case report of a boy with therapy-resistant disseminated JXG who was treated with systemic chemotherapy and received 3 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) from an unrelated donor. The post-transplant period was complicated by acute graft vs host disease and lymphoproliferative disease caused by Epstein-Barr virus. Currently, almost 7.5 years after the first transplantation, the boy is in complete remission with full donor chimerism and without symptoms of JXG. The presented data confirm rare observations that allo-HSCT can lead to durable remission of systemic JXG, which warrants its use in life-threatening, therapy-resistant subtypes of disease.

Introduction Ewing sarcoma (ES) is one of the most frequent malignant tumor of bones in children and adolescents. The final results of applied treatments stay still unsatisfactory. This is why introducing of new diagnostic tools like Fourier Transform Infrared (FTIR) spectroscopy into ES research is so important. Purpose The aim of this study was to establish the possibility of FTIR spectra detection from ES bone samples without preceding deparaffinization, and thus extension of Depciuch et al. research studies (2016) of bones with Ewing sarcoma. Material and methods A total 20 specimen of bones obtained from 10 patients with Ewing sarcoma were analyzed. A half of them was sampled before start of treatment as diagnostic biopsy specimen and rest from the resected tumor after neoadjuvant chemotherapy completion. FTIR spectroscopy (range 1100–3500 cm −1 ) (Vertex 70 Bruker spectrometer) was used for the specimen analysis. Every specimen was examined before and after deparaffinization procedure in triplicate. Results The presence of wax does not affect the surface area, absorbance, half-width or peak position observed in the spectrum peaks in the every analyzed sample. However, in the case of peak at 1234 cm −1 in deparaffinized cancerous tissues the statistically significant differences in the value of absorbance, surface area and half-width (FWHM) compared to paraffin cancerous tissues were observed but without significant impact on the final interpretation. The analysis function of the dielectric imaginary Ɛi (ω) confirm that the Lorentz function parameters for the individual peaks are the same so they do not depend from the sample preparation. Conclusions The spectra obtained from paraffin and deparaffinized bone tissues samples do not differ significantly. Paraffin dewaxing procedure is not necessary before bone specimen FTIR spectroscopy assessment what reduces the risk of tissue damage and adulterated spectrum, and gives some economical advantages.

Fourier transform infrared (FTIR) spectroscopy is a highly sensitive, non-invasive analytical technique that can provide information about molecular changes in a biological sample. FTIR spectrum is a sum of the frequencies of many biomolecules which reveals a biochemical fingerprint for mineral identification, and can be analyzed for information about the mineral structure of malignant cells. This gives us the potential to differentiate tumor cells from normal cells in the early stage of relapse, before the tumor cells would be detectable in light microscopy. Ewing sarcoma (ES) is the second most common malignant bone tumor found in children and adolescents. ES affects annually almost 3 persons/1,000,000 mostly children and young adults under 20 years of age annually. ES originates from primitive, low-differentiated neuroectodermal cells. The current standard of therapy for ES is the surgical resection of the primary tumor and metastasis in combination with the chemo- and radiotherapy. The aim of this study was to compare the spectra of ES bone samples and the spectra of normal bone tissues, analyzed before and after induction chemotherapy, by means of FTIR spectroscopy. Six patients with ES affecting bones aged 5.5–16.5 years (median age 11.2 years), who were treated between 2011 and 2015, were included to the study. In all analyzed patients, the diagnosis of ES and the assessment of response to the chemotherapy were performed according to the Euro-EWING-2008 protocol. The Fourier transform infrared spectroscope (FT-IR; Vertex 70v from Bruker) was used in this study. Tissue specimens were applied to the attenuated total reflection (ATR) in the infrared (IR) radiation from the mid-infrared range using a single-reflection snap ATR crystal diamond. In the FTIR spectra we observed a shift in the wave number of the phosphate ion (from 3 to 26 [cm−1]) associated with the presence of tumor tissue. After chemotherapy, a change of the FTIR spectrum was associated with the ES’s histopathological response. In patients with a high ratio of the necrotic cells in the tumor (>90% of cells) after chemotherapy, we showed a shift of the peak ⧹ absorption bands to the higher wave numbers. In contrast, in patients with a poor chemotherapy response ( The results showed that analysis of the spectrum changes of tissue specimens in ES can be helpful in the assessment of clinical response to cancer therapy. It seems that FTIR spectroscopy is a valuable tool for his purpose. The issue awaits full elucidation in further studies on larger groups of patients with ES.

Background Patients with Ewing sarcoma have a dismal outcome. Maintenance treatment with trofosfamide has been proposed as an effective regimen for same paediatric malignancies. Aim We sought to evaluate the schedule of trofosfamide for patients with high-risk primary bone Ewing sarcoma. Materials and methods Fifteen patients with primary bone Ewing sarcoma received treatment with trofosfamide (750 mg/m2 p.o. days 1-10) every 28 days. All patients hod standard tumour imaging and laboratory evaluation. All toxicities were documented. Results A tatal of 90 cycles (median 5 cycles/patient) were administered. A complete response was maintained in nine patients, while six patients had disease progression during treatment Median time to progression was 7.9 months (range 1.8 to 4.6). Eleven patients (73.3%) are alive including nine with no evidence of disease with a median follow-up of 3.9 years (range 7.4 to 7.6). All patients with active disease at the start of the trofosfamide treatment died. There were no significant toxicities. Conclusions Treatment with trofosfamide is well-tolerated and could have a role to maintain response in patients with primary bone Ewing sarcoma. Further studies are needed to better define the use of this regimen in the upfrront management of those patients.

Background: Improved outcome prediction is vital for the delivery of risk-adjusted, appropriate and effective care to paediatric patients with Ewing sarcoma&mdash, the second most common paediatric malignant bone tumour. Fourier transform infrared (FTIR) spectroscopy of tissues allows the bulk biochemical content of a biological sample to be probed and makes possible the study and diagnosis of disease. Methods: In this retrospective study, FTIR spectra of sections of biopsy-obtained bone tissue were recorded. Twenty-seven patients (between 5 and 20 years of age) with newly diagnosed Ewing sarcoma of bone were included in this study. The prognostic value of FTIR spectra obtained from Ewing sarcoma (ES) tumours before and after neoadjuvant chemotherapy were analysed in combination with various data-reduction and machine learning approaches. Results: Random forest and linear discriminant analysis supervised learning models were able to correctly predict patient mortality in 92% of cases using leave-one-out cross-validation. The best performing model for predicting patient relapse was a linear Support Vector Machine trained on the observed spectral changes as a result of chemotherapy treatment, which achieved 92% accuracy. Conclusion: FTIR spectra of tumour biopsy samples may predict treatment outcome in paediatric Ewing sarcoma patients with greater than 92% accuracy.

Streszczenie Histiocytoza z komórek Langerhansa (LCH) jest rzadką chorobą, u podłoża której może leżeć występowanie zaburzeń w szlaku kinaz aktywowanych mitogenami (MAPK). Obecnie wiadomo, że występowanie powyższych nieprawidłowości łączy się zazwyczaj z bardziej agresywną formą choroby, częstszą opornością na konwencjonalną chemioterapię, a także z większym prawdopodobieństwem wznowy oraz progresji. Od niedawna istnieje możliwość zastosowania w leczeniu pacjentów z LCH inhibitorów BRAF, jednak nie ma obecnie jasnych wytycznych co do kryteriów włączenia powyższej terapii. Niewiele jest też danych literaturowych dotyczących bezpieczeństwa stosowania tego typu preparatów u małoletnich pacjentów. W pracy prezentujemy dziewczynkę z ciężką postacią histiocytozy z komórek Langerhansa niereagującą na leczenie konwencjonalne, u której ustąpienie objawów choroby uzyskano dopiero po włączeniu wemurafenibu. Przypadek ten pokazuje konieczność poszerzania diagnostyki również o badania molekularne oraz możliwość zastosowania leczenia celowanego w tej grupie pacjentów.

Ewing sarcoma (ES) is the second most common pediatric malignant bone tumor with a wide spectrum of clinical presentations. Although metastatic disease to the lungs is often the cause of death, isolated lung metastases at diagnosis are not frequent. The specific role of chemotherapy, surgery, and lung radiation has not been clearly defined. We investigated prognostic factors and the impact of the different treatment modalities in a cohort of patients with ES with isolated lung metastases.Thirty-eight patients with ES and isolated lung metastases were treated using modern multimodal therapy during the period 2000-2014. According to the imaging characteristics of lung nodules patients were allocated into one of four treatment groups: "0" without nodules, "1" one solitary nodule of0.5cm or several nodules of0.3cm, "2" solitary nodule of 0.5-1cm or multiple nodules of 0.3-0.5cm, "3" one pulmonary/pleural nodule of1cm, or more than one nodule of0.5cm. Factors predictive of outcome were analyzed. Overall survival was estimated by Kaplan-Meier methods and compared using long-rank test and Cox models.Treatment of the lung metastases was performed in 23 cases (60.5%): twenty patients underwent lung surgery, 6 of them received additional postoperative whole lung radiation; three patients received lung radiation only. Malignant cells were found in all lung nodules of patients from group "3", in 5 (62.5%) patients from group "2", and none of the group "1". There was a correlation between histological response of the primary tumor and outcome. Three-year estimates of EFS and OS were 45.19% and 60.7%, respectively. Patients with good response measured by chest CT had significantly better EFS than patients with poor response (81% vs. 27.66%, respectively, p=0.006).Metastatectomy may have a role in the treatment of highly selected patients with ES and isolated lung metastases depending on the histologic response to therapy. Further studies are needed to better define the use of surgery and the response-adapted criteria in the upfront management of this population.

e23503 Background: Ewing Sarcoma is a rare type of aggressive tumor that occurs in bones or in the soft tissue around the bones. The multidisciplinary approach chemotherapy (CHT), radiotherapy (RTH) and surgery (S) is the standard of care. The aim of our study was to analyze prognostic factors and treatment results in patients with Ewing Sarcoma. Methods: 504 patient with Ewing sarcoma treated between 1998 and 2019, F:M 1:1.34, with metastases at presentation was 195 patients (39%), axial localization was in 277 patients (55%). All patient were treated with multimodal treatment based on chemotherapy, radiotherapy and surgery. Kaplan-Meier estimator, log rank test and multivariate Cox model were used for statistical analysis. Results: Five year overall survival (5y-OS) was 54% (CI:49-60%), prognostic factors were: gender (5y-OS for females and males equal to 63% and 48%, respectively), age (5y-OS stratified patients between < 10y; 10-15y; 15-25 and 25+ was 65%, 70%, 41% and 55%;p < 0.001), metastases (5y-OS in group with M1 was 31% and in M0 - 70%; p < 0.001), type of local treatment (5y-OS in group CHT/S/RTH was 61%, CHT/S 59%, only RTH 50% and palliative treatment without local treatment equals 12%; p < 0.001). Multivariate Cox analysis revealed death hazard dependence on gender (male vs. female; HR = 1.80; p < 0.01), metastatic status (M1 vs. M0; HR = 2.91; p < 0.001), bone/bone marrow involvement (present vs. absent; HR = 2.10; p < 0.01) and chemotherapy regime (other vs. VIDE/VAI; HR = 0.69; p = 0.049). Conclusions: The treatment results in Ewing sarcoma are significantly better in children than in adults, which can be related to the more intensive chemotherapy regiments applied. The treatment should be provided in referral centers and based on up-to-dated guideline.

11523 Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .

The differential diagnosis of Ewing sarcoma and osteomyelitis can be challenging and can lead to delays in treatment with possibly devastating results. In this retrospective, small-cohort study we demonstrate, that the Fourier Transformed Infrared (FTIR) spectra of osteomyelitis bone tissue can be differentiated from Ewing sarcoma and normal bone tissue sampled outside tumour area. Significant differences in osteomyelitis samples can be seen in lipid and protein composition. Supervised learning using a quadratic discriminant analysis classifier was able to differentiate the osteomyelitis samples with high accuracy. FTIR spectroscopy, alongside routine radiological and histopathological methods, may offer an additional tool for the differential diagnosis of osteomyelitis and ES.

Patients with metastatic, progressive, or recurrent bone tumors have a dismal outcome. Sorafenib has been proposed as an effective salvage regimen for some malignancies. Thus, we sought to evaluate this approach for young patients with relapsed or refractory bone tumors. Twelve patients with refractory bone tumors (two with Ewing sarcoma, two with chondrosarcoma, and eight with osteosarcoma) received salvage treatment with sorafenib. All patients had standard tumor imaging and laboratory evaluation. All toxicities were documented. At the time of the beginning of sorafenib treatment median age among 12 patients was 18 years (range 4.1–27.9 years), eight were male, and eight had osteosarcoma. All received sorafenib because of relapse. Seven patients were treated parallel to other standard chemotherapy. Overall response rate was 75%. Median time to sorafenib time to progression for patients with osteosarcoma was 4 months (range 1.8–7.9 months). Four patients (33%) are alive, in that two with no evidence of disease with a median follow-up of 41 months (range 26.5–60.9 months). The estimated 5 year overall survival (OS) for the whole group was 64.49%. There were no serious toxicities. Sorafenib is well-tolerated in young patients with bone tumors, and particularly could be an option for patients with metastatic disease and refractory osteosarcoma. Sorafenib only allows to extend OS and different procedures are needed to achieve permanent remission. This regimen deserves further investigation in the upfront management of patients with high-risk bone tumors.

Ewing sarcoma is the second most common type of primary bone cancer and predominantly affects children and young people. Improved outcome prediction is key to delivering risk-adjusted, appropriate and effective care to cancer patients. Advances in the Fourier Transform Infrared (FTIR) spectroscopy of tissues enable it to be a non-invasive method to obtain information about the biochemical content of any biological sample. In this retrospective study, attenuated tissue reflection FTIR spectroscopy of biopsy samples from paediatric patients reveals spectral features that are diagnostic for Ewing Sarcoma. Furthermore, our results suggest that spectral features such as these may be of value for the prediction of treatment outcome independent to well-known, routinely used risk factors.

Background With advances in cancer care, more young women with Ewing sarcoma (ES) survive after treatment. Thus, we sought to analyze the ovarian function in prepubertal, pubertal and postpubertal females and young women receiving multimodal therapy for ES, and to identify patients at risk of infertility on whom fertility preservation would be indicated. Procedures Twenty-seven female survivors of ES were included in this retrospective multiinstitutional study. Patients were classified into four groups according to the treatment received: chemotherapy (CHT) without pelvic radiation (pRT), chemotherapy and pRT, CHT and autologous hematopoietic cell stem rescue (aHSCT) without pRT, and CHT + pRT + aHSCT. The ovarian function and fertility outcomes were analyzed. Results At a median follow-up of 5.7 years from diagnosis, and at median age at follow-up of 16.3 years, 67% of the survivors had premature ovarian insufficiency, including all patients receiving pelvic RT and 87.5% of patients who underwent aHSCT, independent of chemoprotection. Thirty-seven percent of patients had a clinical syndrome of premature menopause. The relative risk (RR) of premature ovarian insufficiency of a survivor was 3.9 (p 0.03) for pRT, and 2.4 (p 0.07) for aHSCT. On multivariate analysis, radiation therapy was a significant predictor of higher risk of premature ovarian insufficiency over chemotherapy alone. Conclusions A large proportion of women receiving multimodal therapy for ES develop premature ovarian insufficiency. Patients and guardians should be informed about the reproductive potential and strategies for preservation of ovarian function should be considered individually. Pediatr Blood Cancer 2015;62:341–345. © 2014 Wiley Periodicals, Inc.

Background Pelvic Ewing sarcoma (ES) is commonly associated with a worse prognosis. Large size and location limit local control options to radiation therapy, and local recurrences are common. We evaluated the impact of hemipelvectomy and radiation on outcomes, including function. Materials and methods Thirty-nine patients (median age 13.5years) with ES of the pelvis and sacral bones were treated during the period 2000–2012. Fifteen were treated with definitive radiotherapy (RT), 9 patients underwent hemipelvectomy alone, and 15 were treated with combined hemipelvectomy and RT. Results Twenty patients (51.2%) are alive with a median follow-up 3.2years from diagnosis. Median time from diagnosis to relapse was 1.3years. Three-year estimates of EFS and OS were 47% and 61%, respectively. Patients treated with surgery or surgery with RT had better outcome than patients treated with RT only (3-year OS 78% or 81% vs . 36%, respectively, p=0.00083). The outcome of patients with pelvic ES treated with hemipelvectomy was not significantly different from the outcome of all patients with Ewing sarcoma treated on the national Polish protocol. Conclusions Internal hemipelvectomy offers good chances of cure for patients with pelvic ES, with a reasonable rate of complications and good function.

Background Ewing sarcoma (ES) is the second most common paediatric malignant bone tumor. Advances in multi-disciplinary care have resulted in significant improvement in cure rates over the last decades. However, the generalization of those results in countries traditionally excluded from large cooperative trials has yet to be demonstrated. We report the results of modern multi-disciplinary care for patients with ES in Poland. Procedures One hundred and thirty-two patients with ES were treated using modern multi-modal therapy during the period 2000–2009. Overall survival was estimated by Kaplan–Meier methods and compared using long-rank test and Cox models. Factors predictive of outcome in our setting were analyzed to identify distinct risk groups that could help identify areas for improvement. Results The median age at the time of diagnosis was 12.3 years. With a median follow-up of 5.0 years, the 5-year event-free survival (EFS) and OS estimates for localized disease were 54.88% and 68.29%, respectively. For patients with metastatic disease, 5-year EFS and OS estimates were 36% and 42%, respectively. There was no correlation between age and stage or site. Patients with localized, non-pelvic disease had better outcome than patients with axial tumors (71% vs. 44%, respectively, P = 0.00073). Treatment failure was associated with stage, pelvic primary, poor histological response, and type of local control. Conclusions Successful treatment of ES requires optimal systemic and local therapy. We were able to replicate the results of modern multi-modal protocols. Validation of current treatment protocols in countries with more limited cancer treatment resources is required. Pediatr Blood Cancer 2014;61:2170–2174. © 2014 Wiley Periodicals, Inc.

Background Patients with metastatic, progressive or recurrent Ewing sarcoma (ES) have a dismal outcome. The combination of irinotecan and temozolomide has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination with vincristine for patients with relapsed and refractory ES. Materials and Methods Twenty-two patients with relapsed or refractory ES were treated with the combination of vincristine (1.5 mg/m2 i.v. day 1), irinotecan (50 mg/m2/day i.v. days 1–5) and temozolomide (125 mg/m2/day p.o. days 1–5) (VIT) during the period 2008–2012. All toxicities were documented. Results A total of 91 cycles (median 4.1 cycles/patient) were administered. A complete response (CR) was achieved in five patients, partial response (PR) in seven patients, stable disease (SD) in three patients, and progression disease (PD) in seven patients, with an overall response rate of 68.1%. Median time to progression was 3.0 months (range 1.1–37.1 months). Five patients (22.7%) are alive with no evidence of disease with a median follow-up of 10.3 months (range 2.1–46.5); four of them received consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplant after responding to VIT. Outcome was better for patients with relapsed ES compared with patients who progressed to initial therapy (estimated 2 year overall survival 36.4% vs. 0%, respectively). There were no significant toxicities. Conclusions The shorter, 5-day VIT regimen is an active and well-tolerated regimen in refractory ES. This combination deserves further investigation in the upfront management of patients with metastatic disease. Pediatr Blood Cancer 2013;60:1621–1625. © 2013 Wiley Periodicals, Inc.

Purpose. To check whether primary involvement of brain/spinal cord by bone/soft tissue sarcomas’ metastases in children is as rare as described and to present various morphological forms of bone/soft tissue sarcomas’ CNS metastases. Methods. Patients with first diagnosis in 1999–2014 treated at single center were included with whole course of disease evaluation. Brain/spinal canal magnetic resonance imaging (MRI)/computed tomography were performed in cases suspicious for CNS metastases. Extension from skull/vertebral column metastases was excluded. Results. 550 patients were included. MRI revealed CNS metastases in 19 patients (incidence 3.45%), 14 boys, aged 5–22 years. There were 12/250 osteosarcoma cases, 2/200 Ewing’s sarcoma, 1/50 chondrosarcoma, 3/49 rhabdomyosarcoma (RMS), and 1/1 malignant mesenchymoma. There were 10 single metastases and 7 cases of multiple ones; in 2 RMS cases only leptomeningeal spread in brain and spinal cord was found. Calcified metastases were found in 3 patients and hemorrhagic in 4. In one RMS patient there were numerous solid, cystic, hemorrhagic lesions and leptomeningeal spread. Conclusions. CNS metastases are rare and late in children with bone/soft tissue sarcomas, although in our material more frequent (3.45%) than in other reports (0.7%). Hematogenous spread to brain and hemorrhagic and calcified lesions dominated in osteosarcoma. Ewing sarcoma tended to metastasize to skull bones. Soft tissue sarcomas presented various morphological forms.